Insulitis in human diabetes: a histological evaluation of donor pancreases

Aims/hypothesis

According to the consensus criteria developed for type 1 diabetes, an individual can be diagnosed with insulitis when ≥ 15 CD45⁺ cells are found within the parenchyma or in the islet–exocrine interface in ≥ 3 islets. The aim of this study was to determine the frequency of individuals with type 2 diabetes fulfilling these criteria with reference to non-diabetic and type 1 diabetic individuals.

Methods

Insulitis was determined by examining CD45⁺ cells in the pancreases of 50, 13 and 44 organ donors with type 2 diabetes, type 1 diabetes and no diabetes, respectively. CD3⁺ cells (T cells) infiltrating the islets were evaluated in insulitic donors. In insulitic donors with type 2 diabetes, the pancreases were characterised according to the presence of CD68 (macrophages), myeloperoxidase (MPO; neutrophils), CD3, CD20 (B cells) and HLA class I hyperstained islets. In all type 2 diabetic donors, potential correlations of insulitis with dynamic glucose-stimulated insulin secretion in vitro or age, BMI, HbA_1c or autoantibody positivity were examined.

Results

Overall, 28% of the type 2 diabetic donors fulfilled the consensus criteria for insulitis developed for type 1 diabetes. Of the type 1 diabetic donors, 31% fulfilled the criteria. None of the non-diabetic donors met the criteria. Only type 1 diabetic donors had ≥ 15 CD3⁺ cells in ≥ 3 islets. Type 2 diabetic donors with insulitis also had a substantial number of CD45⁺ cells in the exocrine parenchyma. Macrophages constituted the largest fraction of CD45⁺ cells, followed by neutrophils and T cells. Of type 2 diabetic pancreases with insulitis, 36% contained islets that hyperstained for HLA class I. Isolated islets from type 2 diabetic donors secreted less insulin than controls, although with preserved dynamics. Insulitis in the type 2 diabetic donors did not correlate with glucose-stimulated insulin secretion, the presence of autoantibodies, BMI or HbA_1c.

Conclusions/interpretation

The current definition of insulitis cannot be used to distinguish pancreases retrieved from individuals with type 1 diabetes from those with type 2 diabetes. On the basis of our findings, we propose a revised definition of insulitis, with a positive diagnosis when ≥ 15 CD3⁺ cells, not CD45⁺ cells, are found in ≥ 3 islets.

     

Pancreas Pathology During the Natural History of Type 1 Diabetes

Purpose of review

We provide an overview of pancreas pathology in type 1 diabetes (T1D) in the context of its clinical stages.

Recent findings

Recent studies of pancreata from organ donors with T1D and non-diabetic donors expressing T1D-associated autoantibodies reveal pathological changes/disease mechanisms beyond the well-known loss of β cells and lymphocytic infiltrates of the islets (insulitis), including β-cell stress, dysfunction, and viral infections. Pancreas pathology evolves through disease stages, is asynchronous, and demonstrates a chronic disease that remains active years after diagnosis. Critically, β-cell loss is not complete at onset, although young age is associated with increased severity.

Summary

The recognition of multiple pathogenic alterations and the chronic nature of disease mechanisms during and after the development of T1D inform improved clinical trial design and reveal additional targets for therapeutic manipulation, in the context of an expanded time window for intervention.

     

The Effect of Age on the Progression and Severity of Type 1 Diabetes: Potential Effects on Disease Mechanisms

Purpose of Review

To explore the impact of age on type 1 diabetes (T1D) pathogenesis.

Recent Findings

Children progress more rapidly from autoantibody positivity to T1D and have lower C-peptide levels compared to adults. In histological analysis of post-mortem pancreata, younger age of diagnosis is associated with reduced numbers of insulin containing islets and a hyper-immune CD20^hi infiltrate. Moreover compared to adults, children exhibit decreased immune regulatory function and increased engagement and trafficking of autoreactive CD8⁺ T cells, and age-related differences in β cell vulnerability may also contribute to the more aggressive immune phenotype observed in children. To account for some of these differences, HLA and non-HLA genetic loci that influence multiple disease characteristics, including age of onset, are being increasingly characterized.

Summary

The exception of T1D as an autoimmune disease more prevalent in children than adults results from a combination of immune, metabolic, and genetic factors. Age-related differences in T1D pathology have important implications for better tailoring of immunotherapies.

     

The effect of interleukin-22 treatment on autoimmune diabetes in the NOD mouse

Aims/hypothesis

The aim of this study was to determine whether therapy with the cytokine IL-22 could be used to prevent the development of, or treat, autoimmune diabetes in the NOD mouse.

Methods

Six-week-old NOD mice were administered bi-weekly either recombinant mouse IL-22 (200 ng/g) or PBS (vehicle control) intraperitoneally until overt diabetes was diagnosed as two consecutive measurements of non-fasting blood glucose ≥ 11 mmol/l. At this time, NOD mice in the control arm were treated with LinBit insulin pellets and randomised to bi-weekly therapeutic injections of either PBS or IL-22 (200 ng/g) and followed until overt diabetes was diagnosed, as defined above.

Results

IL-22 therapy did not delay the onset of diabetes in comparison with the vehicle-treated mice. We did not observe an improvement in islet area, glycaemic control, beta cell residual function, endoplasmic reticulum stress, insulitis or macrophage and neutrophil infiltration as determined by non-fasting blood glucose, C-peptide and histological scoring. Therapeutic administration of IL-22 did not reduce circulating lipopolysaccharide, a marker of impaired gut mucosal integrity.

Conclusions/interpretation

Our study suggests that, at this dosing regimen introduced either prior to overt diabetes or at diagnosis of diabetes, recombinant mouse IL-22 therapy cannot prevent autoimmune diabetes, or prolong the honeymoon period in the NOD mouse.

     

Diabetes Awareness and Knowledge Among Latinos: Does a Usual Source of Healthcare Matter?

Objective

To provide national prevalence estimates of usual source of healthcare (USHC), and examine the relationship between USHC and diabetes awareness and knowledge among Latinos using a modified Andersen model of healthcare access.

Participants

Three thousand eight hundred and ninety-nine Latino (18-years or older) participants of the Pew Hispanic Center/Robert Wood Johnson Foundation Hispanic/Latino Health survey from the 48 contiguous United States.

Design

Cross-sectional, stratified, random sample telephone interviews.

Methods

Self-reported healthcare service use was examined in regression models that included a past-year USHC as the main predictor of diabetes awareness and knowledge. Anderson model predisposing and enabling factors were included in additional statistical models.

Results

Significant differences in USHC between Latino groups were found with Mexican Americans having the lowest rates (59.7%). USHC was associated with significantly higher diabetes awareness and knowledge (OR=1.24; 95%CI=1.05-1.46) after accounting for important healthcare access factors. Men were significantly (OR=0.64; 95%CI=0.52-0.75) less informed about diabetes than women.

Conclusion

We found important and previously unreported differences between Latinos with a current USHC provider, where the predominant group, Mexican Americans, are the least likely to have access to a USHC. USHC was associated with Latinos being better informed about diabetes; however, socioeconomic barriers limit the availability of this potentially valuable tool for reducing the risks and burden of diabetes, which is a major public health problem facing Latinos.

     

BMI Trajectories as a Harbinger of Pre-Diabetes or Underdiagnosed Diabetes: an 18-Year Retrospective Cohort Study in Taiwan

Background

Although prior studies have examined BMI trajectories in Western populations, little is known regarding how BMI trajectories in Asian populations vary between adults with and without diabetes.

Objective

To examine how BMI trajectories vary between those developing and not developing diabetes over 18 years in an Asian cohort.

Design

Multilevel modeling was used to depict levels and rates of change in BMI for up to 18 years for participants with and without self-reported physician-diagnosed diabetes.

Participants

We used 14,490 data points available from repeated measurements of 3776 participants aged 50+ at baseline without diabetes from a nationally representative survey of the Taiwan Longitudinal Study on Aging (TLSA1989-2007).

Main Measures

We defined development of diabetes as participants who first reported diabetes diagnoses in 2007 but had no diabetes diagnoses at baseline. We defined the reference group as those participants who reported the absence of diabetes at baseline and during the entire follow-up period.

Key Results

When adjusted for time-varying comorbidities and behavioral factors, higher level and constant increases in BMI were present more than 6.5 years before self-reported diabetes diagnosis. The higher BMI level associating with the development of diabetes was especially evident in females. Within 6.5 years prior to self-reported diagnosis, however, a wider range of decreases in BMI occurred (β_diabetes?=?1.294, P?=?0.0064; β_{diabetes*time}?=?0.150, P?=?0.0327; β_{diabetes*time} ²?=??0.008, P?=?0.0065). The faster rate of increases in BMI followed by a greater decline was especially prominent in males and individuals with BMI ≧24.

Conclusions

An unintentional decrease in BMI in sharp contrast to the gradually rising BMI preceding that time may be an alarm for undiagnosed diabetes or a precursor to developing diabetes.

     

Diabetes,Depression, and Cognition: a Recursive Cycle of Cognitive Dysfunction and Glycemic Dysregulation

Purpose of Review

The study aims to examine the effects of diabetes and depression on executive functioning (EF) and to review the effects of EF deficits on diabetes management.

Recent Findings

Both type 2 diabetes and depression influence EF, and in turn, EF has an impact on diabetes management.

Summary

Individuals with both comorbidities (i.e., diabetes and depression) experience greater deficits in EF than individuals with just one of the morbidities (i.e., depression or diabetes). The disruption in EF results in poor diabetes management and poor emotion regulation which ultimately increases the probability of a recursive cycle of depression and hyperglycemia. This recursive cycle can ultimately lead to diabetes-related complications.

     

IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells

Aims/hypothesis

IFN-α, a cytokine expressed in human islets from individuals affected by type 1 diabetes, plays a key role in the pathogenesis of diabetes by upregulating inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression, three hallmarks of islet histology in early type 1 diabetes. We tested whether expression of these mediators of beta cell loss is reversible upon IFN-α withdrawal or IFN-α pathway inhibition.

Methods

IFN-α-induced MHC class I overexpression, ER stress and inflammation were evaluated by flow cytometry, immunofluorescence and real-time PCR in human EndoC-βH1 cells or human islets exposed to IFN-α with or without the presence of Janus kinase (JAK) inhibitors. Protein expression was evaluated by western blot.

Results

IFN-α-induced expression of inflammatory and ER stress markers returned to baseline after 24–48 h following cytokine removal. In contrast, MHC class I overexpression at the cell surface persisted for at least 7 days. Treatment with JAK inhibitors, when added with IFN-α, prevented MHC class I overexpression, but when added 24 h after IFN-α exposure these inhibitors failed to accelerate MHC class I return to baseline.

Conclusions/interpretation

IFN-α mediates a long-lasting and preferential MHC class I overexpression in human beta cells, which is not affected by the subsequent addition of JAK inhibitors. These observations suggest that IFN-α-stimulated long-lasting MHC class I expression may amplify beta cell antigen presentation during the early phase of type 1 diabetes and that IFN-α inhibitors might need to be used at very early stages of the disease to be effective.

     

PIWI-interacting RNAs as novel regulators of pancreatic beta cell function

Aims/hypothesis

P-element induced Wimpy testis (PIWI)-interacting RNAs (piRNAs) are small non-coding RNAs that interact with PIWI proteins and guide them to silence transposable elements. They are abundantly expressed in germline cells and play key roles in spermatogenesis. There is mounting evidence that piRNAs are also present in somatic cells, where they may accomplish additional regulatory tasks. The aim of this study was to identify the piRNAs expressed in pancreatic islets and to determine whether they are involved in the control of beta cell activities.

Methods

piRNA profiling of rat pancreatic islets was performed by microarray analysis. The functions of piRNAs were investigated by silencing the two main Piwi genes or by modulating the level of selected piRNAs in islet cells.

Results

We detected about 18,000 piRNAs in rat pancreatic islets, many of which were differentially expressed throughout islet postnatal development. Moreover, we identified changes in the level of several piRNAs in the islets of Goto–Kakizaki rats, a well-established animal model of type 2 diabetes. Silencing of Piwil2 or Piwil4 genes in adult rat islets caused a reduction in the level of several piRNAs and resulted in defective insulin secretion and increased resistance of the cells to cytokine-induced cell death. Furthermore, overexpression in the islets of control animals of two piRNAs that are upregulated in diabetic rats led to a selective defect in glucose-induced insulin release.

Conclusions/interpretation

Our results provide evidence for a role of PIWI proteins and their associated piRNAs in the control of beta cell functions, and suggest a possible involvement in the development of type 2 diabetes.

Data availability

Data have been deposited in Gene Expression Omnibus repository under the accession number GSE93792. Data can be accessed via the following link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=ojklueugdzehpkv&acc=GSE93792

     

Immunmodulierende Wirkung von Vitamin D und Typ-1-Diabetes

Objective

Vitamin D is not only essential for bone metabolism, but also has an additional immune-modulating effect on the immune system, which may play a role in the pathogenesis of several endocrine diseases.

Aim

In this review, we debate the effects and recommendations of vitamin D supplementation, especially in the context of the nonclassical effects.

Results

Evidence from animal model and epidemiological studies supports a role for vitamin D in many endocrine conditions. Vitamin D supplementation may play a role in the prevention of type 1 diabetes mellitus.

Conclusions

Although observational studies support a potential role of vitamin D in endocrine disease, high-quality evidence from clinical trials to establish a place for vitamin D supplementation in optimizing endocrine health are lacking. Based on observational studies, vitamin D deficiency should probably be avoided in individuals at high risk of developing type 1 diabetes, specifically in early life.

     

Implementation of a Chronic Illness Model for Diabetes Care in a Family Medicine Residency Program

INTRODUCTION

While the Chronic Care Model (CCM) has been shown to improve the care of patients with chronic illnesses, primary care physicians have been unprepared in its use, and residencies have encountered challenges in introducing it into the academic environment.

AIM

Our residency program has implemented a diabetes management program modeled on the CCM to evaluate its impact on health outcomes of diabetic patients and educational outcomes of residents.

SETTING

University-affiliated, community-based family medicine residency program.

PROGRAM DESCRIPTION

Six residents, two faculty clinicians, and clinic staff formed a diabetes management team. We redesigned the outpatient experience for diabetic patients by incorporating elements of the CCM: multidisciplinary team care through planned and group visits; creation of a diabetes registry; use of guidelines-based flow sheets; and incorporation of self-management goal-setting. Residents received extensive instruction in diabetes management, quality improvement, and patient self-management.

PROGRAM EVALUATION

We achieved overall improvement in all metabolic and process measures for patients, with the percentage achieving HbA1c, LDL, and BP goals simultaneously increasing from 5.7% to 17.1%. Educational outcomes for residents, as measured by compliance with review of provider performance reports and self-management goal-setting with patients, also significantly improved.

DISCUSSION

Through a learning collaborative experience, residency programs can successfully incorporate chronic care training for residents while addressing gaps in care for patients with diabetes.

     

Germinal centre frequency is decreased in pancreatic lymph nodes from individuals with recent-onset type 1 diabetes

Aims/hypothesis

Pancreatic lymph nodes (PLNs) are critical sites for the initial interaction between islet autoantigens and autoreactive lymphocytes, but the histology of PLNs in tissue from individuals with type 1 diabetes has not been analysed in detail. The aim of this study was to examine PLN tissue sections from healthy donors compared with those at risk of, or with recent-onset and longer-duration type 1 diabetes.

Methods

Immunofluorescence staining was used to examine PLN sections from the following donor groups: non-diabetic (n=15), non-diabetic islet autoantibody-positive (n=5), recent-onset (≤1.5 years duration) type 1 diabetes (n=13), and longer-duration type 1 diabetes (n=15). Staining for CD3, CD20 and Ki67 was used to detect primary and secondary (germinal centre-containing) follicles and CD21 and CD35 to detect follicular dendritic cell networks.

Results

The frequency of secondary follicles was lower in the recent-onset type 1 diabetes group compared with the non-diabetic control group. The presence of insulitis (as evidence of ongoing beta cell destruction) and diagnosis of type 1 diabetes at a younger age, however, did not appear to be associated with a lower frequency of secondary follicles. A higher proportion of primary B cell follicles were observed to lack follicular dendritic cell networks in the recent-onset type 1 diabetes group.

Conclusions/interpretation

Histological analysis of rare PLNs from individuals with type 1 diabetes suggests a previously unrecognised phenotype comprising decreased primary B cell follicle frequency and fewer follicular dendritic cell networks in recent-onset type 1 diabetes.

     

Financial Incentives and Diabetes Disease Control in Employees: A Retrospective Cohort Analysis

Background

Many employers offer worksite wellness programs, including financial incentives to achieve goals. Evidence supporting such programs is sparse.

Objective

To assess whether diabetes and cardiovascular risk factor control in employees improved with financial incentives for participation in disease management and for attaining goals.

Design

Retrospective cohort study using insurance claims linked with electronic medical record data from January 2008–December 2012.

Participants

Employee patients with diabetes covered by the organization’s self-funded insurance and propensity-matched non-employee patient comparison group with diabetes and commercial insurance.

Intervention

Financial incentives for employer-sponsored disease management program participation and achieving goals.

Main Measures

Change in glycosylated hemoglobin (HbA1c), low-density lipoprotein (LDL), systolic blood pressure (SBP), and weight.

Results

A total of 1092 employees with diabetes were matched to non-employee patients. With increasing incentives, employee program participation increased (7 % in 2009 to 50 % in 2012, p?<?0.001). Longitudinal mixed modeling demonstrated improved diabetes and cardiovascular risk factor control in employees vs. non-employees [HbA1c yearly change ?0.05 employees vs. 0.00 non-employees, difference in change (DIC) p <0.001]. In their first participation year, employees had larger declines in HbA1c and weight vs. non-employees (0.33 vs. 0.14, DIC p?=?0.04) and (2.3 kg vs. 0.1 kg, DIC p?<?0.001), respectively. Analysis of employee cohorts corresponding with incentive offerings showed that fixed incentives (years 1 and 2) or incentives tied to goals (years 3 and 4) were not significantly associated with HbA1c reductions compared to non-employees. For each employee cohort offered incentives, SBP and LDL also did not significantly differ in employees compared with non-employees (DIC p?>?0.05).

Conclusions

Financial incentives were associated with employee participation in disease management and improved cardiovascular risk factors over 5 years. Improvements occurred primarily in the first year of participation. The relative impact of specific incentives could not be discerned.

     

Diabetes und Hypertonie

Background

Diabetes mellitus is a disease which leads to vascular damage resulting in subsequent severe cardiovascular complications, such as myocardial infarction and stroke. This process is aggravated by coexisting hypertension.

Objective

This analysis gives a review of the latest study results on prognosis, blood pressure targets, drug therapy and interventional therapy in patients with diabetes and hypertension. Selected studies published in recent years with practical relevance for patients with diabetes and hypertension are presented.

Summary

Patients with simultaneous diabetes and hypertension have a poorer prognosis and a higher cardiovascular risk compared to patients with diabetes but without hypertension. Patients with diabetes and hypertension benefit from interventional blood pressure therapy

     

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

Aims/hypothesis

Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B₁) in a cohort of individuals with TRMA-related diabetes.

Methods

We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire.

Results

We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3–24]) and median age at diabetes onset was 10 months (IQR 5–27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3–10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p?=?0.042), at genetic testing (p?=?0.01) and when starting thiamine (p?=?0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day.

Conclusions/interpretation

In TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent.

Data availability

SLC19A2 mutation details have been deposited in the Decipher database (https://decipher.sanger.ac.uk/).

     

Thrombozytenfunktion

Background and objectives

Patients with diabetes mellitus are at increased cardiovascular risk. While arteriosclerotic lesions have long been recognized as the underlying cause, more recent studies suggest alterations in the coagulation system to be equally important in this context.

Materials and methods

A systematic PubMed search was performed.

Results

In patients with diabetes mellitus, alterations in the coagulation system play a pivotal role. This not only contributes to the increased cardiovascular risk but also explains the low or nonresponse to antiplatelet therapy. These alterations in the coagulation system include changes in platelet and fibrin clot function. This is reflected by the recommendation of the 2013 ESC guidelines on antiplatelet therapy in diabetes.

Conclusions

This article provides an overview of pathophysiological alterations in coagulation of patients with diabetes mellitus and the recommended antiplatelet therapy in the presence of coronary artery disease.

     

B cell depletion reduces T cell activation in pancreatic islets in a murine autoimmune diabetes model

Aims/hypothesis

Type 1 diabetes is a T cell-mediated autoimmune disease characterised by the destruction of beta cells in the islets of Langerhans, resulting in deficient insulin production. B cell depletion therapy has proved successful in preventing diabetes and restoring euglycaemia in animal models of diabetes, as well as in preserving beta cell function in clinical trials in the short term. We aimed to report a full characterisation of B cell kinetics post B cell depletion, with a focus on pancreatic islets.

Methods

Transgenic NOD mice with a human CD20 transgene expressed on B cells were injected with an anti-CD20 depleting antibody. B cells were analysed using multivariable flow cytometry.

Results

There was a 10 week delay in the onset of diabetes when comparing control and experimental groups, although the final difference in the diabetes incidence, following prolonged observation, was not statistically significant (p?=?0.07). The co-stimulatory molecules CD80 and CD86 were reduced on stimulation of B cells during B cell depletion and repopulation. IL-10-producing regulatory B cells were not induced in repopulated B cells in the periphery, post anti-CD20 depletion. However, the early depletion of B cells had a marked effect on T cells in the local islet infiltrate. We demonstrated a lack of T cell activation, specifically with reduced CD44 expression and effector function, including IFN-γ production from both CD4⁺ and CD8⁺ T cells. These CD8⁺ T cells remained altered in the pancreatic islets long after B cell depletion and repopulation.

Conclusions/interpretation

Our findings suggest that B cell depletion can have an impact on T cell regulation, inducing a durable effect that is present long after repopulation. We suggest that this local effect of reducing autoimmune T cell activity contributes to delay in the onset of autoimmune diabetes.

     

Loss of prohormone convertase 2 promotes beta cell dysfunction in a rodent transplant model expressing human pro-islet amyloid polypeptide

Aims/hypothesis

A contributor to beta cell failure in type 2 diabetes and islet transplants is amyloid formation by aggregation of the beta cell peptide, islet amyloid polypeptide (IAPP). Similar to the proinsulin processing pathway that generates insulin, IAPP is derived from a prohormone precursor, proIAPP, which requires cleavage by prohormone convertase (PC) 1/3 and PC2 in rodent pancreatic beta cells. We hypothesised that loss of PC2 would promote beta cell death and dysfunction in a rodent model of human beta cell proIAPP overexpression.

Methods

We generated an islet transplant model wherein immune-deficient mouse models of diabetes received islets expressing amyloidogenic human proIAPP and lacking PC2, leading to restoration of normoglycaemia accompanied by increased secretion of human proIAPP. Blood glucose levels were analysed for up to 16 weeks in transplant recipients and grafts were assessed for islet amyloid and beta cell number and death.

Results

Hyperglycaemia (blood glucose >16.9 mmol/l) returned in 94% of recipients of islets expressing human proIAPP and lacking PC2, whereas recipients of islets that express human proIAPP and normal PC2 levels remained normoglycaemic for at least 16 weeks. Islet graft failure was accompanied by a ～20% reduction in insulin-positive cells, yet the degree of amyloid deposition and beta cell apoptosis was similar to those of controls expressing human proIAPP with functional PC2 levels.

Conclusions/interpretation

PC2 deficiency in transplanted mouse islets expressing human proIAPP promotes beta cell loss and graft failure. Our data suggest that impaired NH₂-terminal processing and increased secretion of human proIAPP promote beta cell failure.